Effect of rs1058240 polymorphism in 3'-UTR of GATA3 gene on potential binding of miRNAs and its association with RRMS risk: bioinformatics analysis and case-control study.

Abstract

Aim: Multiple sclerosis is believed to be an autoimmune disease that is influenced by T helper (Th) cell differentiation. GATA3 plays an important role in reducing the development and severity of MS by shifting the differentiation of Th cells to Th2 and regulatory T cells while inhibiting the differentiation of Th1 and Th17 cells. Considering the functional role of rs1058240 SNP in the 3'-UTR of GATA3 mRNA, the association of target SNP with the risk of RRMS was examined.

Methods: Genomic DNA was extracted from whole blood samples of 200 RRMS patients and 226 healthy individuals as a control group. Different genotypes of rs1058240 SNP were determined using the RFLP-PCR technique. Statistical analysis was performed using SPSS software and χ2 and logistic regression tests. The stability of GATA3 mRNA secondary structures and the binding patterns of GATA3-miRNAs with different alleles were evaluated using RNAfold and RNAhybrid programs, respectively.

Results: The results indicated that the GATA3 rs1058240 G allele (p value = 0.010, OR = 1.45, CI = 1.09-1.93) and GG genotype (adjusted p value = 0.017, OR = 2.27, 95%CI = 1.16-4.44) increased the risk of RRMS, particularly in women (adjusted p value = 0.006, OR = 2.99, 95%CI = 1.37-6.52). Bioinformatics analysis revealed that although the allelic variation of this polymorphism had only a slight effect on mRNA stability (-177 to -177.20), the G allele significantly increased miRNA binding strength and miRNA-mRNA thermodynamic stability for hsa-miR-337-5p, hsa-miR-4445-3p, hsa-miR-4485-3p, hsa-miR-95-3p (ΔMFE > 0) compared to the A allele.

Conclusion: The G allele and GG genotype of rs1058240 in GATA3 mRNA 3'-UTR were found to be risk factors for increasing the susceptibility to RRMS.